In vitro Interactions Between the Oral Absorption Promoter, Sodium Caprate (C10) and S. typhimurium in Rat Intestinal Ileal Mucosae

Cox, Alyssa B.; Rawlinson, Lee-Anne Betty; Baird, Alan W.; Bzik, Victoria A; Brayden, David J.

doi:10.1007/s11095-007-9354-9

Cited by 22 publications

(14 citation statements)

References 43 publications

(45 reference statements)

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“…Capric acid and C 10 have established antibacterial-and antiviral properties at similar concentrations to those required for absorption-promotion [207][208][209]. We found that C 10 does not increase the translocation of E. coli across Caco-2 monolayers, while the detergent, Triton X-100, significantly increased E. coli flux at concentrations that modulate permeability (Fig.…”

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 59%

“…perfringens and S. sonnei [207,208]. Capric acid also has antimicrobial activity against a panel of bacteria that are frequently found in clinical microbiology [211].…”

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 99%

“…In a screen of 13 bacterial isolates, C 10 inhibited growth and biofilm formation at concentrations that are used to promote absorption in cell cultures and in vivo models (Unpublished data, Rawlinson L. and Brayden DJ). In addition to antimicrobial activity, C 10 has been shown to reduce adhesion of S. typhimurium to isolated ileal mucosa of rats [207]. Capric acid has antiviral activity against a number of enveloped viruses [209], antifungal activity [211] as well as anti-protozoal activity against the common intestinal parasite, Giardia duodenalis [212].…”

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 99%

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Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 59%

“…perfringens and S. sonnei [207,208]. Capric acid also has antimicrobial activity against a panel of bacteria that are frequently found in clinical microbiology [211].…”

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 99%

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 99%

See 1 more Smart Citation

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

Self Cite

197

176

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“…Concerns over colonic co-absorption of bystander pathogens, including bacteria, bacterial toxins and viruses in the presence of PEs have thus far not been vindicated, but studies have been largely restricted to in vitro models (34). Of interest is that similar C 10 concentrations required for PE in vivo inhibited adhesion of Salmonella typhimurium in isolated rat intestinal mucosae and indeed were bactericidal against S. typhimurium and several gram-positive and -negative bacteria (35). Overall, it would be preferable for MCFAs to have no effect on the intestinal microbiota, either toxic, innocuous or probiotic species.…”

Section: Discussionmentioning

confidence: 99%

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

Brayden

Walsh

2014

AAPS J

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ABSTRACT. 10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC 11 , would improve intestinal permeation similar to the established enhancer, sodium caprate (C 10 ), but without the toxicity of the parent saturated MCFA, decylenic acid (C 11 ). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C 11 >C 10 =uC 11 . Five to ten millimolars of the three agents reduced TEER and increased the Papp of [ 14 C]-mannitol across Caco-2 monolayers and rat intestinal mucosae, a concentration that matched increases in plasma membrane permeability seen in HCS. Although C 11 was the most efficacious enhancer in vitro, it damaged monolayers and tissue mucosae more than the other two agents at similar concentrations and exposure times and was therefore not pursued further. Rat jejunal and colonic in situ intestinal instillations of 100 mM C 10 or uC 11 with FITC-dextran 4000 (FD4) solutions yielded comparable regional enhancement ratios of~10 and 30%, respectively, for each agent with acceptable tissue histology. Mini-tablets of uC 11 and FD4 however delivered more FD4 compared to C 10 -FD-4 mini-tablets in both regions, as reflected by a statistically higher AUC, and with no evidence of membrane perturbation. The unsaturated bond in uC 11 therefore confers a reduction in lipophilicity and cytotoxicity compared to C 11 , and the resulting permeation enhancement is on a par with or superior to that of C 10 , a key component of formulations in current phase II oral peptide clinical trials.

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“…S. typhimurium was not able to translocate across isolated rat ileal mucosa upon co-exposure to C 10 (1-30mM). 61 The lack of facilitation by C 10 may in part be due to known anti-bacterial effects of MCFA, which may pose questions on its possible unbalancing effects on gut microbiota, although this would be unlikely to occur due to the rapid absorption of MCFAs in the gut. In relation to other oral peptide technologies based on nanotechnology, when LPS was administered to mice orally for 7 consecutive days with or without co-administration of a chitosan-based insulin-entrapped nanoparticle (Fig 4), there was no increase in LPS serum levels nor damage to hepatic tissue.…”

Section: Pe-induced Intestinal Permeability Of Lps and Xenobioticsmentioning

confidence: 99%

Safety concerns over the use of intestinal permeation enhancers: A mini-review

2016

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Intestinal permeation enhancers (PEs) are key components in »12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo-and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

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In vitro Interactions Between the Oral Absorption Promoter, Sodium Caprate (C10) and S. typhimurium in Rat Intestinal Ileal Mucosae

Abstract: C(10) does not promote the permeation of a common bacterium across isolated intestinal tissue upon acute co-exposure. It prevents S. typhimurium attachment to epithelia and impedes growth of a range of different bacterial strains.

Cited by 22 publications

References 43 publications

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

Safety concerns over the use of intestinal permeation enhancers: A mini-review

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